Avicenna's Canon of Medicine: a review of analgesics and anti-inflammatory substances

Naturally occurring substances mentioned in medieval medical literatures currently have, and will continue to have, a crucial place in drug discovery. Avicenna was a Persian physician who is known as the most influential medical writers in the Middle ages. Avicenna`s Canon of Medicine, the most famous books in the history of medicine, presents a clear and organized summary of all the medical knowledge of the time, including a long list of drugs. Several hundred substances and receipts from different sources are mentioned for treatment of different illnesses in this book. The aim of the present study was to provide a descriptive review of all anti-inflammatory and analgesic drugs presented in this comprehensive encyclopedia of medicine. Data for this review were provided by searches of different sections of this book. Long lists of anti-inflammatory and analgesic substances used in the treatment of various diseases are provided. The efficacy of some of these drugs, such as opium, willow oil, curcuma, and garlic, was investigated by modern medicine; pointed to their potent anti-inflammatory and analgesic properties. This review will help further research into the clinical benefits of new drugs for treatment of inflammatory diseases and pain.


Introduction
Abu Ali al-Ḥusain Ebn Abdullah Ebn Sina (980 -1037 AD), known in the West as Avicenna, was a Persian physician who is known as the most influential medical writers in the medieval period. Between the thirteenth to the seventeenth centuries, Avicenna held a high place in Western medical studies, ranking as an acknowledged supremacy. His works had a crucial impact on the modern medicine and at some universities continued to be used for teaching up to the nineteenth century (Brentjes, 1980;Weisser, 2011).
However, most medicinal substances prescribed by Avicenna remain largely unexamined (Gorji, 2003). The antiinflammatory and analgesic medicaments are a heterogeneous group of substances, which share definite remedial actions and side effects. The search for new pharmacologically active antiinflammatory and analgesic drugs offered by medieval medical literatures has led to the discovery of some clinically useful drugs. These compounds, during the last two centuries, have played a crucial role as effective remedies of various human diseases as well as in understanding of basic pathophysiology of some diseases (Gorji and Khaleghi Ghadiri, 2001;Gorji and Khaleghi Ghadiri, 2002;Khaleghi Ghadiri and Gorji, 2004;Vakili and Gorji, 2007;Bayan et al., 2013). Despite progress in the development of therapy in recent years, effective and potent antiinflammatory and analgesic drugs are still required for the treatment of different diseases. The aim of the present study was to provide a descriptive review of all antiinflammatory and analgesic drugs noted in the Canon of Avicenna. Data for this review were provided by searches of different sections of this book translated in Persian (Avicenna, 1988). It is hoped that this manuscript will help further research into the clinical benefits of these compounds for treatment of inflammatory diseases.

Anti-inflammatory and analgesic drugs
Avicenna (1988) describes the signs and symptoms (pain, swelling, redness, fever, impaired functions, etc.) of different inflammatory diseases (such as pneumonia, rhinitis, otitis, dermatitis, etc.) and their treatment with several substances with different modes of action. These drugs were advised to use as prophylactic or therapeutic. Many of these drugs were prescribed for different inflammatory disease, although some of those were advised for a certain disorder. The strategies for treatment of pain and inflammation were divided into the measures of acute and chronic diseases. Furthermore, these drugs were classified for treatment of mild, moderate, or severe conditions in each disorder. It is also noted that some of these drugs in certain conditions act as anti-inflammatory of analgesic drugs, in other condition my provoke pain or inflammation. The antiinflammatory and analgesic drugs listed in the Canon include plants, animal products, and minerals. Avicenna emphasized the importance of the dose and the route of administration and defined a schedule for drug application. Drugs were also taken via skin, oral, nasal, or rectal routes as well as by inhalation (Table).
Some of the medicaments suggested by Avicenna for treatment of inflammation and pain are well-recognized dugs in modern medicine. Many of these compounds are under experimental or clinical investigations for their probable therapeutic effects. However, most of these drugs remain largely unexamined.

Well recognized anti-inflammatory and analgesic drugs
Papaver somniferum Opium (Papaver somniferum) was advised for treatment of arthralgia, sciatica, gout, muscle pain and nerve injury, otitis, blepharitis, urogenital pain, abdominal pain, uterine pain, colic, postoperative pain, and chronic pain in the Canon. In 1680, Sydenham was noted opium: "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium" (Yaksh and Wallace, 2011).
Administration of opiate in Europe increased rapidly in the 18th century (Miller and Tran, 2000). Opium and its derivatives have been used as the most widely analgesics for severe pain since the early 1800s (Hamilton and Baskett, 2000). Nowadays, application of several opioids is considered effective for the treatment of various forms of headaches (Gorji and Khaleghi Ghadiri 2001), postoperative pain (Hamilton and Baskett, 2000), neuropathic pain (Berrios et al., 2008), and different chronic pain syndromes (Vallejo et al., 2011). Opium also plays a crucial role in our understanding of basic mechanism of pain (Lipman, 1990).

Salix spp.
In the Canon, administration of willow oil (Salix spp.) was recommended for treatment of headache, osteitis, ophthalmitis, orbital injury, liver disorders and jaundice, and dysmenorrhea. In the first half of the 19th century salicin, the principal active constituent of willow oil was extracted from the willow bark and later salicylic acid was obtained. Today, the synthetically produced preparations of salicylic acid are well-known analgesic, anti-inflammatory and antipyretic drug (Amann and Peskar, 2002).
Acetylsalicylic acid is recommended as an analgesic and prophylactic in different types of headaches [4], and alleviates dysmenorrhea (Pendergrass et al., 1985). Furthermore, it has been suggested that regular aspirin use (more than 15 times per month) may be associated with a lower prevalence of non-alcoholic fatty liver disease among men and older patients (Shen et al., 2014).

Curcuma longa
Curcuma (Curcuma longa) is advised for treatment of different inflammatory diseases and pain in the Canon. Promising effects of curcuma have been reported in patients with various pro-inflammatory diseases, including oncologic disorders, cardiovascular disease, rheumatologic diseases, chronic anterior uveitis, gastrointestinal inflammatory diseases (Crohn's disease, ulcerative proctitis and colitis, irritable bowel disease, pancreatitis, gastric inflammation as well as ulcer, and cholecystitis), lupus nephritis, ischemic brain injuries, and acquired immunodeficiency syndrome (Gupta et al., 2013;Tamaddonfard, 2013;Arshami et al., 2013;Ghosh et al., 2014).

Cannabis sativa
Cannabis (Cannabis sativa) was prescribed for the alleviation of severe headache as well as treatment for degenerative bone and joint diseases, ophthalmitis, general edema, infectious wounds, gout, and uterine pain. The major active component of cannabis, tetrahydrocannabinols, in addition to other constituents of cannabis has been shown to possess anti-nociceptive properties (Wilson and Nicoll, 2002).
Cannabinoids alleviate pain by the activation of a brainstem circuit that is required for opioid-mediated analgesia, and modulate basal nociceptive thresholds through the activation of the rostral ventromedial medulla [8]. It has been suggested that cannabinoids may act as an analgesic in migraine pain by inhibition of spreading depression phenomenon (Kazemi et al., 2012). Different constituents of cannabis have been suggested to be useful in the treatment of intervertebral disc degeneration (Silveira et al., 2014), endometriosis (Sanchez et al., 2012), and breast cancer (Behrend, 2013). Cannabis has been suggested to be used to treat patients with cancer who do not adequately treated with other analgesics and anti-emetics (Nauck et al., 2004).

Allium sativum
Garlic (Allium sativum) was recommended by Avicenna in his book for treatment of acute inflammation, chronic and malignant wounds, arthritis and gout, sciatica, common cold, headache, earache, severe eye pain, acute cough, lung disease with hematemesis, gastroenteritis, and liver diseases. Anti-inflammatory effect is a well-known property of this plant. Garlic and its bioactive components protect the hepatocytes from several toxic agents and act as antimicrobial, antifungal, and antiviral substances (Bayan et al., 2014). Diallyl disulfide, a major organosulfur compound in garlic oil, has been shown to a useful substance in treatment of respiratory inflammation (Shin et al., 2013). Administration of garlic have been suggested for treatment of common cold (Allan and Arroll, 2014), arterial occlusive disease (Jepson et al., 2013), migraine headache (Roussos and Hirsch, 2014;Marschollek et al., 2014), and prevention of different tumors (Bayan et al., 2014).

Matricaria chamomilla
Avicenna advised to use chamomile (Matricaria chamomilla) for treatment of headache, edema, conjunctivitis, jaundice, chronic fever, lithiasis, amenorrhea, toothache, and muscle tightness. Chamomile is recommended to relieve itching and inflammation and facilitate healing of peristomal skin lesions in patients undergone the gastrointestinal or urinary surgeries (Charousaei et al., 2011).
The fluid extract from chamomile reduced pain of aphthous ulcers in patients suffering from recurrent aphthous stomatitis (Ramos-e-Silva et al., 2006). It is hypothesized that chamomile flavonoids and polyphenols due to its antiinflammatory properties via the inhibition of pro-inflammatory biomarkers in macrophages, inhibition of endogenous prostaglandin E2 levels, and reduction of nitric oxide values may alleviate migraine pain (Zargaran et al., 2014). Chamomile modulates phase I and phase II drug metabolizing enzymes in the liver (Maliakal and Wanwimolruk, 2001), improves endometrial tissue arrangements (Farideh et al., 2010), and alleviate pain and edema present in various inflammatory conditions (Tomić et al., 2014) in animal experiments. The antiinflammatory effect of chamomile is suggested to be mainly due its essential oils, such as bisabololand, chamazulene and matricin, possibly via inhibition of histamine release and the production of prostaglandin (Safayhi et al., 1994;Miller et al., 1996;Srivastava et al., 2010).

Malus orientalis
Apple (Malus orientalis) is advised for treatment of acute general edema, muscle pain, abscess, otitis, purulent wounds, toothache, chronic cough and pneumonia, abdominal pain, and intestinal inflammation as well as for prevention of headache by Avicenna. The apple contains polyphenols with a large variability in their structures, which are stored in vacuoles and chromoplasts (Francini and Sebastiani, 2013).
Antioxidant reactions of phytochemicals inhibit the oxidation of harmful substances and act as radical catcher. Reactive oxygen species are noxious in a large amount and cause cell damage by reaction with lipids, proteins and deoxyribonucleic acid (Mladenka et al., 2010). Secondary plant metabolites and polyphenols have anti-inflammatory, anticarcinogenic, anti-microbial, anti-oxidant, and anti-thrombotic effects (Scalbert et al., 2005;Jelodarian et al., 2013). Apple polysaccharide extract is suggested to prevent colitis-associated colon cancer via the inhibition of TLR4/MD2-mediated signaling and the inhibition of NF-κBmediated inflammatory signaling pathways (Zhang et al., 2015). Apple flavonols in combination with fish oil inhibited the production of pro-inflammatory mediators and significantly improved blood lipid profiles in rats with diet-induced hyperlipidemia and lipopolysaccharideinduced acute inflammation (Sekhon-Loodu et al., 2014).
High-flavonoid apple was associated with decreases in the transcription levels of inflammation-linked genes for interleukin-2 receptor, chemokine receptor 2, chemokine ligand 10, and chemokine receptor 10 as well as in production of prostaglandin E2 (Espley et al., 2014).
The protective effect of frankincense against rheumatoid arthritis is suggested evident due to the decrease in arthritis scoring and bone histology in a collagen induced arthritis model in rats (Umar et al., 2014). Aflapin, a novel Boswellia-derived anti-inflammatory product, significantly inhibited interleukins 1β-induced death of human primary chondrocytes and improves production of glycosaminoglycan in human chondrocytes (Sengupta et al., 2011).

Cinnamomum camphora
Camphor (Cinnamomum camphora) is advised for treatment of headache and arthralgia as well as against inflammation in different organs. Camphor inhibited heat-sensitive transient receptor potential vanilloid subtype 1 (TRPV1) and several other related channels, which may underlie the analgesic effects of camphor (Xu et al., 2005). Camphor activated cultured primary keratinocytes (contained heat-activated receptors), and this effect was abolished in TRPV3 null mice (Moqrich et al., 2005).
Phytochemical investigation of Myrrh (Commiphera myrrha) has resulted in identification of more than 300 secondary metabolites which have exhibited a widerange of pharmacological properties that are effective in treatment of inflammatory and infection diseases.
The bioactive steroids guggulsterones have been suggested as a potent inhibitory component on tumor cells and inflammation (Shen et al., 2012). Lavender (Lavendula stoechas) is believed to have a variety of therapeutic and curative properties in the Canon. In a placebocontrolled clinical trial, inhalation of lavender oil was suggested as an effective and safe treatment in acute management of migraine attacks (Sasannejad et al., 2012). Lavender inhibited some inflammatory processes, such as lipopolysaccharideinduced inflammatory reaction (Koulivand et al., 2013).
Ethanolic and aqueous extracts of saffron (Crocus sativus), another analgesic and anti-inflammatory drug mentioned in the Canon, have been suggested as a useful substances in treatment of different kinds of neuropathic pain and acetaminophen toxicity (Amin and Hosseinzadeh, 2012;Omidi et al., 2014. Several strategies have been used for development of new drugs. One of these strategies is the use, development and improvement of existing medicines, like natural healing substances, which have been used long to treat the illnesses in traditional medicine. Although some of anti-inflammatory and analgesic substances advised by Avicenna in the Canon are used by modern medicine, the exact mechanism of their action as well as biochemical and pharmacological values needs more investigations. Several other drugs are still unexamined, which have the potential for further investigations and discovery of new drugs against inflammatory diseases and pain.

Acknowledgment
Authors appreciated financial supports of Iran National Science Foundation (INSF) and Shefa Neuroscience Center (Doctor Thesis 97112).